Acquired immunodeficiency syndrome (AIDS) is caused by a retrovirus identified as the human immunodeficiency virus (HIV). A number of immunologic abnormalities have been described in AIDS including abnormalities in B-cell function, abnormal antibody response, defective monocyte cell function, impaired cytokine production, depressed natural killer and cytotoxic cell function, and defective ability of lymphocytes to recognize and respond to soluble antigens. Other immunologic abnormalities associated with AIDS have been reported. Among the more important immunologic defects in patients with AIDS is the depletion of the T4 helper/inducer lymphocyte population.
In spite of the profound immunodeficiency observed in AIDS, the mechanism(s) responsible for immunodeficiency are not clearly understood. Several postulates exist. One accepted view is that defects in immune responsiveness are due to selective infection of helper T cells by HIV resulting in impairment of helper T-cell function and eventual depletion of cells necessary for a normal immune response. In vitro and in vivo studies showed that HIV can also infect monocytes which are known to play an essential role as accessory cells in the immune response. HIV may also result in immunodeficiency by interfering with normal cytokine production in an infected cell resulting in secondary immunodeficiency as for example, IL-1 and IL-2 deficiency. An additional means of HIV-induced immunodeficiency consists of the production of factors which are capable of suppressing the immune response. None of these models resolves the question of whether a component of HIV per se, rather than infection by replicative virus, is responsible for the immunologic abnormalities associated with AIDS.
The HIV env protein has been extensively described, and the amino acid and RNA sequences encoding HIV env from a number of HIV strains are known (Modrow, S. et al., J. Virology 61(2): 570 (1987). The HIV virion is covered by a membrane or envelope derived from the outer membrane of host cells. The membrane contains a population of envelope glycoproteins (gp 160) anchored in the membrane bilayer at their carboxyl terminal region. Each glycoprotein contains two segments. The N-terminal segment, called gp120 by virtue of its relative molecular weight of about 120 kD, protrudes into the aqueous environment surrounding the virion. The C-terminal segment, called gp41, spans the membrane. gp120 and gp 41 are covalently linked by a peptide bond that is particularly susceptible to proteolytic cleavage, see e.g. McCune et al., EPO Application No. 0 335 635, priority 28 Mar. 88 and references cited therein.
Several approaches to an AIDS vaccine have been proposed, including inactivated and attenuated virus vaccines, subunit vaccines from virus-infected cells, recombinantly produced viral antigens, vaccines based on synthetic peptides, anti-idiotypic vaccines, and viral carrier-based vaccines, however no vaccination study published to date has provided protection against challenge with virus. Several reviews of HIV vaccine development have been published, e.g. Lasky, Critical Reviews in Immunology 9(3): 153–172 (1989), Newmark, Nature 333:699 (23 Jun. 23, 1988), and Fauci et al., Annals of Internal Medicine 110(5): 41–50 (1 Mar. 1989).
The use of whole (killed or attenuated) virus presents several problems, including the safety to workers producing the vaccine, and risk to those inoculated from incomplete inactivation of virus, or reversion of an attenuated virus to an active, virulent form. Both peptide and subunit vaccines could potentially have difficulty in obtaining their native conformations, and may only elicit humoral responses, perhaps not eliciting cell-mediated immunity. Another key difficulty in developing an AIDS vaccine lies in the variability of HIV from strain to strain, as well as in the same strain over time.
Of the proteins encoded by the HIV genome, the molecules most frequently used for vaccine development are located on the surface of the virus. They mediate virus attachment and the spread of the virus by cell-to-cell fusion (syncytia formation) and are the viral proteins most accessible to immune attack. Currently, gp120 is considered to be the best candidate for a subunit vaccine, because: (i) gp120 is known to possess the CD4 binding domain by which HIV attaches to its target cells, (ii) HIV infectivity can be neutralized in vitro by antibodies to gp120, (iii) the majority of the in vitro neutralizing activity present in the serum of HIV infected individuals can be removed with a gp120 affinity column, and (iv) the gp120/gp41 complex appears to be essential for the transmission of HIV by cell-to-cell fusion.
Vaccination of animals of several species with recombinant vectors that express HIV env are described in the literature. These vaccination attempts elicited strain-specific humoral immune responses as well as cell-mediated responses (see e.g. Van Eendenburg et al., AIDS Research and Human Retroviruses 5(1):41–50 (1989); Hu et al., Nature 320:537–540 (1986); Chakrabarti et al., Nature 320:535–537 (1986); Zarling et al., Nature 323:344–346 (1986); Hu et al., Nature 328:721–724 (1987); Zagury et al., Nature 326:249–250 (1987); Zagury et al., Nature 322:728–731 (1988).
Chimpanzees are the only nonhuman primate infectable with HIV and therefore they are the closest-to-human animal model system for vaccine-challenge study. Despite the promise suggested by the immune responses discussed above, published vaccine studies have all failed to protect chimpanzees from infection by HIV (see e.g. Hu et al., Nature 328:721–724 (1987) (vaccinia virus-HIV env recombinant vaccine); Arthur et al., J. Virol. 63(12): 5046–5053 (1989) (purified gp120); Berman et al., Proc. Natl. Acad. Sci. USA 85:5200–5204 (1988) (recombinant envelope glycoprotein gp120); and Prince et al., Proc. Natl. Acad. Sci. USA 85:6944–6948 (1988) (purified human HIV immune globulin).
The Simian Immunodeficiency Virus (SIV) is a lentivirus which is indigenous to healthy African monkeys; SIV is the animal lentivirus most closely related to HIV. Letvin et al., Vaccines 87, Cold Spring Harbor Lab 209–213 (1987) discloses an unsuccessful attempt to immunize macaque monkeys against SIV using an inactivated virus vaccine. Desrosiers et al., Proc. Natl. Acad. Sci. USA 86:6353–6357 (1989) reported protection of two of six macaque monkeys against SIV by immunization with a detergent-disrupted whole virus SIV vaccine. Murphey-Corb et al., Science 246:1293–1297 (1989) disclose protection of eight of nine rhesus macaques against a SIV challenge by vaccination with a formalin-inactivated SIV whole virus vaccine.
It is therefore an object of this invention to provide vaccines capable of eliciting a protective immune response against HIV infection.
It is a further object of this invention to provide methods for preparing such HIV vaccines, and appropriate immunization schedules for the prevention and treatment of AIDS.
Other objects, features, and characteristics of the present invention will become apparent upon consideration of the following description and the appended claims.